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Relationship between Metabolic Fates and Antitumor Activities of Thiopurines

( Wellcome Research Laboratories, Burroughs Wellcome & Co. [U.S.A.]), Inc., Tuckahoe, New York; and Duke University School of Medicine, Durham, North Carolina)

The urinary metabolites of a number of S-substituted derivatives of 6-mercaptopurine (6-MP) have been determined in both mouse and man. The metabolic fates of 6-MP, 6-(1-methyl-4-nitro-5-imidazolyl)thiopurine (B.W. 57-322) and 6-(2,4-dinitrophenyl)thiopurine (B.W. 59-318) are similar with respect to the amounts of free 6-MP and 6-thiouric acid excreted by both species. The dealkylation of 6-methylthiopurine is greater than that of 6-propylthiopurine in man, whereas in the mouse the opposite appears to be true. In man a predominant metabolite of the alkylthiopurines is the corresponding 6-alkylsulfinyl-8-hydroxypurine; in the mouse this pathway of inactivation is minor. The relative antitumor activities of these compounds can be correlated with their metabolic fates in the two species.

The catabolism of 6-MP to thiouric acid and sulfate is diminished by the administration of an inhibitor of xanthine oxidase, 4-hydroxypyrazolo(3,4-d)pyrimidine. This enzyme inhibition results in a several-fold potentiation in the antitumor activities of both 6-MP and 6-chloropurine when tested against Adenocarcinoma 755 in mice, and an improvement in the chemotherapeutic index of 6-chloropurine and possibly 6-MP in this system.

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